Macrophage-targeting gene silencing orchestrates myocardial microenvironment remodeling toward the anti-inflammatory treatment of ischemia-reperfusion (IR) injury

Yao Wang; Mengying Hou; Shanzhou Duan; Ziyin Zhao; Xuejie Wu; Yongbing Chen; Lichen Yin

Bioactive Materials (Nov 2022)

Macrophage-targeting gene silencing orchestrates myocardial microenvironment remodeling toward the anti-inflammatory treatment of ischemia-reperfusion (IR) injury

Yao Wang,
Mengying Hou,
Shanzhou Duan,
Ziyin Zhao,
Xuejie Wu,
Yongbing Chen,
Lichen Yin

Affiliations

Yao Wang: Department of Cardiothoracic Surgery, the Second Affiliated Hospital of Soochow University, Suzhou, 215002, China; Institute of Functional Nano and Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, Suzhou, 215123, China; Yancheng First Hospital, Affiliated Hospital of Nanjing University Medical School, Yancheng, 224005, China
Mengying Hou: Institute of Functional Nano and Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, Suzhou, 215123, China
Shanzhou Duan: Department of Cardiothoracic Surgery, the Second Affiliated Hospital of Soochow University, Suzhou, 215002, China; Corresponding author.
Ziyin Zhao: Institute of Functional Nano and Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, Suzhou, 215123, China
Xuejie Wu: Department of Cardiothoracic Surgery, the Second Affiliated Hospital of Soochow University, Suzhou, 215002, China
Yongbing Chen: Department of Cardiothoracic Surgery, the Second Affiliated Hospital of Soochow University, Suzhou, 215002, China; Corresponding author.
Lichen Yin: Institute of Functional Nano and Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, Suzhou, 215123, China; Corresponding author.

Journal volume & issue: Vol. 17
pp. 320 – 333

Abstract

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Ischemia-reperfusion (IR) injury represents a major cause of myocardial dysfunction after infarction and thrombolytic therapy, and it is closely related to the free radical explosion and overwhelming inflammatory responses. Herein, macrophage-targeting nanocomplexes (NCs) are developed to mediate efficient co-delivery of siRNA against MOF (siMOF) and microRNA-21 (miR21) into myocardial macrophages, cooperatively orchestrating the myocardial microenvironment against IR injury. Bioreducible, branched poly(β-amino ester) (BPAE-SS) is designed to co-condense siMOF and miR21 into NCs in a multivalency-reinforced approach, and they are surface-decorated with carboxylated mannan (Man-COOH) to shield the positive surface charges and enhance the serum stability. The final MBSsm NCs are efficiently internalized by myocardial macrophages after systemic administration, wherein BPAE-SS is degraded into small segments by intracellular glutathione to promote the siMOF/miR21 release, finally provoking efficient gene silencing. Thus, cardiomyocyte protection and macrophage modulation are realized via the combined effects of ROS scavenging, inflammation inhibition, and autophagy attenuation, which ameliorates the myocardial microenvironment and restores the cardiac function via positive cellular crosstalk. This study renders promising solutions to address the multiple systemic barriers against in vivo nucleic acid delivery, and it also offers new options for IR injury by manipulating multiple reciprocal bio-reactions.

Published in Bioactive Materials

ISSN: 2452-199X (Online)
Publisher: KeAi Communications Co., Ltd.
Country of publisher: China
LCC subjects: Technology: Electrical engineering. Electronics. Nuclear engineering: Materials of engineering and construction. Mechanics of materials; Science: Biology (General)
Website: https://www.keaipublishing.com/en/journals/bioactive-materials/

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